Catalytic Formal Conjugate Addition: Direct Synthesis of δ-Hydroxynitriles from Nitriles and Allylic Alcohols

Alcohols and nitrile functionalities have widespread applications in biochemical and chemical synthesis. Catalytic transformations involving C-C bond formation relying on unsaturated coupling partners create important pathways for processes in synthetic, material, and medicinal chemistry. The discovery of a simple and selective coupling of nitriles with allylic alcohols catalyzed by a ruthenium pincer complex is described, which tolerates reactive functional groups such as carbamate, sulfonate, olefin, cyano, and trifluoromethyl-substituted benzyl nitriles. Homo allylic alcohols also provided 1,4-addition products following the isomerization of double bonds. Mechanistic studies supported that the allylic alcohols initially undergo selective oxidation by the catalyst to alpha,beta-unsaturated carbonyl compounds followed by 1,4-conjugate addition of benzyl nitriles catalyzed by a base and subsequent catalytic reduction of carbonyl functionality, leading to the formation of delta-hydroxynitrile products. The catalytic cycle of this tandem process is established by density functional theory studies. Remarkably, anipamil drug is successfully synthesized using this catalytic protocol. The utility of the delta-hydroxynitrile products in the synthesis of biologically active molecules and their further functionalization are also demonstrated.

Automated summary

This article describes a simple method for the coupling of nitriles with allylic alcohols catalyzed by a ruthenium pincer complex. Mechanistic studies were conducted to investigate the catalytic cycle. The method demonstrated tolerability towards reactive functional groups such as carbamate, sulfonate, olefin, cyano, and trifluoromethyl-substituted benzyl nitriles. Additionally, the synthesis of anipamil drug and the utility of delta-hydroxynitrile products in the synthesis and functionalization of biologically active molecules were demonstrated.